Abstract

Medication errors and adverse drug reactions are frequent in hospitalized patients. The principle aim of my dissertation was to review the existing data about frequency and risk factors of these findings and to propose measures for their reduction, focusing on the possibilities of hospital pharmacists. In more detail, the aims were: – To review the literature published between 1990 and 2003 for studies reporting incidences of medication errors and/or adverse drug effects in hospitals – To investigate the prevalence of potential drug-drug interactions in ambulatory patients treated with a statin – To propose dosage guidelines for patients with liver disease being treated with antineoplastic drugs. This study was initiated because questions about dose adaptation of antineoplastic drugs are quite frequent in hospital pharmacies In the first study, I analyzed the original publications about medication errors and/or adverse drug reactions in hospitalized patients published between 1990 and 2003, with a focus on frequency, risk factors and avoidance of problems associated with pharmacotherapy. I performed a database search (Medline, Embase) for original articles using the terms „medication error“, „adverse drug reaction“, “adverse event”, „hospital“ and supplemented the articles retrieved by searching review articles for additional references. The analysis revealed that medication errors occur with a frequency of approximately 5% of all drug applications, with a high variability among the 29 studies retrieved. This variability is explained by the way medication errors are detected (systematic screening of patients or charts vs. spontaneous reports) and by the way drugs were administered (intravenous drugs have the highest error frequency). Errors occur along the whole medication process, with application errors accounting for more than 50% of them. Important risk factors are insufficient pharmacological knowledge and work overload of the nursing staff, non-computerized transmission of prescriptions and lack of clinical pharmacists on the wards. Adverse reactions affect approximately 6% of the patients per hospitalization and show a high variability between the 31 studies retrieved. This variability can be explained by different assessment of the frequency of adverse drug reactions and by the wards studied. Risk factors for adverse drug reactions include female sex, age >65 years, polypharmacy and medication errors. These findings allowed me to propose strategies for reducing medication errors, e.g. to improve the knowledge about pharmacology of all persons involved in the medication process, computerization of the entire medication process and the engagement of clinical pharmacists on the wards. In the second study, we performed a cross-sectional analysis of the prevalence of potentially serious drug-drug interactions of ambulatory dyslipidemic patients treated with a statin. Data of patients with dyslipidemia treated with a statin were collected from 242 practitioners from different parts of Switzerland. The medication was screened for potentially harmful DDIs with statins or other drugs using an interactive electronic drug interaction program. We included 2742 ambulatory statin-treated patients (mean age 65.1 ± 11.1 [SD] years; 61.6% males) with 3.2 ± 1.6 (mean±SD) diagnoses and 4.9 ± 2.4 drugs prescribed. Of those, 190 patients (6.9%) had a total of 198 potentially harmful drug-statin interactions. Interacting drugs were fibrates or nicotinic acid (9.5% of patients with drug-statin interactions), CYP3A4- inhibitors (70.5%), digoxin (22.6%) or cyclosporine (1.6%). The proportion of patients with a potential drug-statin interaction was 12.1% for simvastatin, 10.0% for atorvastatin, 3.8% for fluvastatin, and 0.3% for pravastatin. Additionally, the program identified 393 potentially critical non-statin DDIs in 288 patients. Our study showed that CYP3A4 inhibitors are the most frequent cause for potential interactions with statins. As the risk for developing rhabdomyolysis is increased in patients having drug-statin interactions, clinicians should be aware of the most frequently observed drug-statin interactions and how these interactions can be avoided. In the third study, we classified the antineoplastic drugs marketed in Switzerland by the end of 2003 according to their hepatic extraction in order to predict their kinetic behavior in patients with liver disease and to give dose recommendations. Dose adaptation for liver disease is important in patients treated with antineoplastic drugs due to the high prevalence of impaired liver function in this population and the dose-dependent, frequently serious adverse effects of these drugs. We therefore classified the antineoplastic drugs marketed in Switzerland by the end of the year 2004 according to their bioavailability/hepatic extraction in order to predict their kinetic behavior in patients with decreased liver function. This prediction was compared with kinetic studies carried out with these drugs in patients with liver disease. Of the 69 drugs identified, 52 had a predominant extrarenal (in most cases hepatic) metabolism and/or excretion. For 48 drugs, hepatic extraction could be calculated and/or bioavailability was available, allowing classification according to hepatic extraction. For 17 drugs, kinetic studies have been reported in patients with impaired liver function, with the findings generally resulting in quantitative recommendations for adaptation of the dosage. In particular, recommendations are precise for 13 drugs excreted by the bile (e.g. doxorubicin and derivatives, and vinca alkaloids). Validation studies comparing such recommendations with kinetics and/or dynamics of antineoplastic drugs in patients with decreased liver function have not been published, however. The study shows that there are currently not enough data for safe use of antineoplastic drugs in patients with liver disease. We concluded that pharmaceutical companies should be urged to provide kinetic data (especially hepatic extraction) used for classification of such drugs and to conduct kinetic studies for drugs with primarily hepatic me tabolism in patients with impaired liver function allowing to give quantitative advise for dose adaptation. The studies show that medication errors and adverse drug reactions are frequent in hospitalized patients. Medication errors are an important risk factor for avoidable adverse drug reactions. For two of them, drug-drug interactions and dose adaptation in patients with liver disease, we performed studies focusing on the incidence and guidelines for their avoidance, respectively. Hospital pharmacists have an important role both in the prevention and detection of medication errors and adverse drug reactions.